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Gonadotropins are routinely administered to produce multiple oocytes for clinical in vitro fertilization (IVF) treatment, laboratory research, and livestock industries. Studies in mice have shown gonadotropin stimulation using equine chorionic gonadotropin (eCG) affects the endometrium, implantation, and fetal development. Evidence from clinical studies also indicates that stimulation with recombinant human follicle-stimulating hormone (rhFSH) may be detrimental to the endometrium and implantation rates. We investigated the effect of rhFSH in mice on maternal plasma hormone concentrations and uterine gene and protein expression and the effect of a stimulated maternal environment on pregnancy. Adult females were stimulated with rhFSH or eCG, followed by human chorionic gonadotropin (hCG). On day 4 of pseudopregnancy, mice either had embryos transferred to the uterus or were killed, and blood and uterine samples were collected. Pregnancy outcomes were examined on day 15. Gonadotropin stimulation increased plasma progesterone concentrations on day 4 compared with controls, whereas estradiol concentrations were unaffected. Stimulation also reduced uterine leukemia inhibitory factor (Lif) mRNA, but the expression of estrogen and progesterone receptors (Esrl and Pgr), homeobox gene Hoxa10, and Vegf mRNA were unchanged. Furthermore, distribution of uterine PGR protein expression was altered by stimulation, but LIF protein was unchanged. Stimulated embryo transfer recipients had lower pregnancy rates than controls, and fetuses from the rhFSH group had reduced weight, length, and maturity. These results demonstrate that gonadotropin stimulation with rhFSH or eCG alters the preimplantation maternal environment, which results in reduced pregnancy rates and fetal development in the mouse. endometrium; equine chorionic gonadotropin; ovarian stimulation; gonadotropin; mouse

Small size at birth has been associated with an increased risk of central obesity and reduced lean body mass in adult life. This study investigated the time of onset of prenatally induced obesity, which occurs after maternal feed restriction, in the guinea pig, a species that, like the human, develops substantial adipose tissue stores before birth. We examined the effect of maternal feed restriction [70% ad libitum intake from 4 wk before to midpregnancy, then 90% until day 60 gestation (term ~69 days)] on fetal growth and body composition in the guinea pig. Maternal feed restriction reduced fetal (-39%) and placental (-30%) weight at 60 days gestation and reduced liver, biceps muscle, spleen, and thymus weights, relative to fetal weight, while relative weights of brain, lungs, and interscapular and retroperitoneal fat pads were increased. In the interscapular depot, maternal feed restriction decreased the volume density of multilocular fat and increased that of unilocular fat, resulting in an increased relative weight of interscapular unilocular fat. Maternal feed restriction did not alter the relative weight of perirenal fat or the volume density of adipocyte populations within the depot but increased unilocular lipid locule size. Maternal feed restriction in the guinea pig is associated with decreased weight of major organs, including liver and skeletal muscle, but increased adiposity of the fetus, with relative sparing of unilocular adipose tissue. If this early-onset obesity persists, it may contribute to the metabolic and cardiovascular dysfunction that these offspring of feed-restricted mothers develop as adults. pregnancy: adipose tissue: fetus

Maternal nutrient restriction and impaired fetal growth are associated with postnatal insulin resistance, hyperinsulinemia, and glucose intolerance in humans but not consistently in other species, such as the rat or sheep. We therefore determined the effect of mild (85% ad libitum intake/kg body wt) or moderate (70% ad libitum intake/kg body wt) maternal feed restriction throughout pregnancy on glucose and insulin responses to an intravenous glucose tolerance test (IVGTT) in the young adult guinea pig. Maternal feed restriction reduced birth weight (mild and moderate: both P < 0.02) in male offspring. Moderate restriction increased plasma glucose area under the curve (P < 0.04) and decreased the glucose tolerance index ([K.sub.G]) (P < 0.02) during the IVGTT in male offspring compared with those of mildly restricted but not of ad libitum-fed mothers. Moderate restriction increased fasting plasma insulin (P < 0.04, adjusted for litter size) and the insulin response to IVGTT (P < 0.001), and both moderate and mild restriction increased the insulin-to-glucose ratio during the IVGTT (P < 0.003 and P < 0.02) in male offspring. When offspring were classed into tertiles according to birth weight, glucose tolerance was not altered, but fasting insulin concentrations were increased in low compared with medium birth weight males (P < 0.03). The insulin-to-glucose ratio throughout the IVGTT was increased in low compared with medium (P < 0.01) or high (P < 0.05) birth weight males. Thus maternal feed restriction in the guinea pig restricts fetal growth and causes hyperinsulinemia in young adult male offspring, suggestive of insulin resistance. These findings suggest that mild to moderate prenatal perturbation programs postnatal glucose homeostasis adversely in the guinea pig, as in the human. birth weight; intravenous glucose tolerance test; plasma insulin

The liver and skeletal muscles of sheep and rats were analyzed to determine the role of insulin-like growth factor-I (IGF-I) in the expression of IGF-I and IGF-II messenger ribonucleic acids (mRNA) during the fetal stage. Infusion of IGF-I in fetal sheep enhanced the levels of IGF-I in fetal plasma without altering the levels of IGF-II in the fetal blood. Furthermore, intravenous administration of fetal sheep enhanced IGF-I and IGF-II mRNA in the fetal liver indicating the role of IGF-I in mediating hepatic IGF-I and IGF-II synthesis.

Kind, Karen L., Peter M. Clifton, Arkadi I. Katsman, Maria Tsiounis, Jeffrey S. Robinson, and Julie A. Owens. Restricted fetal growth and the response to dietary cholesterol in the guinea pig. Am. J. Physiol. 277 (Regulatory Integrative Comp. Physiol. 46): R1675-R1682, 1999.--Epidemiological studies suggest that retarded growth before birth is associated with increased plasma total and low-density lipoprotein (LDL) cholesterol concentrations in adult life. Thus perturbations of prenatal growth may permanently alter cholesterol metabolism. To determine directly whether restriction of prenatal nutrition and growth alters postnatal cholesterol homeostasis, the plasma cholesterol response to cholesterol feeding (0.25% cholesterol) was examined in adult guinea pig offspring of ad libitum-fed or moderately undernourished mothers. Maternal undernutrition (85% ad libitum intake throughout pregnancy) reduced birth weight (-13%). Plasma total cholesterol was higher prior to and following 6 wk cholesterol feeding in male offspring of undernourished mothers compared with male offspring of ad libitum-fed mothers (P [is less than] 0.05). The influence of birth weight on cholesterol metabolism was examined by dividing the offspring into those whose birth weight was above (high) or below (low) the median birth weight. Plasma total cholesterol concentrations prior to cholesterol feeding did not differ with size at birth, but plasma total and LDL cholesterol were 31 and 34% higher, respectively, following cholesterol feeding in low-compared with high-birth weight males (P [is less than] 0.02). The response to cholesterol feeding in female offspring was not altered by variable maternal nutrition or size at birth. Covariate analysis showed that the effect of maternal undernutrition on adult cholesterol metabolism could be partly accounted for by alterations in prenatal growth. In conclusion, maternal undernutrition and small size at birth permanently alter postnatal cholesterol homeostasis in the male guinea pig. maternal undernutrition; pregnancy; birth weight; plasma cholesterol; low-density lipoprotein cholesterol